Predictors of the usefulness of mirogabalin for neuropathic pain: a single-institution retrospective study.

Mirogabalin is a novel, preferentially selective α2δ-1 ligand to treat neuropathic pain. However, this agent is not always effective for patients with neuropathic pain. We therefore attempted to identify factors that could predict the efficacy of mirogabalin. The study comprised 133 patients given mirogabalin for alleviation of neuropathic pain between April and November 2019 at our hospital. Variables were extracted from medical records for regression analysis of factors associated to alleviation of neuropathic pain. We evaluated the effect of mirogabalin at two weeks after administration. Groups were categorized according to degree of improvement: poor, effective, or very effective. Multivariate ordered logistic regression analysis was conducted to identify predictors for the usefulness of mirogabalin. Threshold measures were analysed using receiver operating characteristic (ROC) curves. Maintenance dose [odds ratio (OR) = 0.90; 95% confidence interval (CI) = 0.84-0.98; P = 0.01], concomitant use of opioids (OR = 0.26, 95% CI = 0.08-0.83; P = 0.023) and Neurotropin® (NTP) (OR = 4.78, 95% CI =1.04-21.93; P = 0.044) were factors significantly correlated to the effect of mirogabalin. ROC curve analysis of the effective group indicated a threshold maintenance dose of≤ 20 mg/day (area under the curve [AUC] = 0.53). In conclusion, maintenance dose (≤ 20 mg), concomitant use of opioids and NTP were identified as predictors for the utility of mirogabalin.

Clinical application of radial magnetic resonance imaging for evaluation of rotator cuff tear.

BACKGROUND: Magnetic resonance imaging is useful for evaluating the rotator cuff, but some tendinous insertions cannot be assessed using oblique sagittal, oblique coronal, and axial magnetic resonance (MR) images because of the presence of the partial volume effect. HYPOTHESIS: The purpose of this study was to determine whether radial-slice MR images could reveal normal rotator cuff insertions and rotator cuff tears more clearly than conventional MR images. PATIENTS AND METHODS: The study included 18 subjects with normal rotator cuffs and 30 with rotator cuff tears. MR images of rotator cuff insertions sliced into radial, oblique coronal, and axial sections were obtained. The extent to which normal rotator cuff insertions and rotator cuff tears were visualized in each of the three MR images was evaluated. RESULTS: The top to posterior portions of the rotator cuff insertions from 0° to 120° could be visualized in the radial MR images. In comparison, the posterior portions of the rotator cuff insertions could not be visualized around 45° in both the oblique coronal and axial MR images. DISCUSSION: These findings demonstrate that radial MR images are superior to the oblique coronal and axial MR images regarding their ability to accurately visualize rotator cuff insertions. Radial MR images also revealed greater detail around 45° in the posterior area of the rotator cuff tears than the oblique coronal and axial MR images. Radial MR images are particularly useful for visualizing clinically important posterosuperior rotator cuff tears. LEVEL OF EVIDENCE: Level III - Diagnostic study.

Three cases of suspected sugammadex-induced hypersensitivity reactions.

Neuromuscular blocking agents have been implicated in 60-70% of anaphylactic events associated with anaesthesia. We report two cases of probable hypersensitivity reaction to sugammadex and an additional suspected but less supported case of possible immune-mediated reaction or other adverse reaction. The patients were given a bolus of sugammadex 100 mg immediately before extubation. In all three patients, a possible allergic reaction was suspected within 4 min of sugammadex administration, but with different degrees of severity. Skin testing was positive in two of these patients. Hypersensitivity to sugammadex unaccompanied by cardiovascular or respiratory symptoms might be missed during the course of anaesthesia. Careful monitoring for possible allergic responses is required in patients who have received sugammadex.

Motor learning of hands with auditory cue in patients with Parkinson's disease.

In the present research, changes in motor cortex function were observed in relation to repetitive, voluntary thumb movement (training) in patients with Parkinson's disease (PD) and normal control subjects. Changes in the direction of thumb movement due to motor evoked potential (MEP) by transcranial magnetic stimulation (TMS), after motor training with and without rhythmic sound, were measured using a strain gauge for 12 patients with PD and 9 normal control subjects. PD patients who experienced the freezing phenomena showed poor change in direction of TMS-induced movement after self-paced movement; however, marked change in direction of TMS-induced movement was observed after training with auditory cue. PD patients who had not experienced the freezing phenomena showed positive effects with the auditory cue, producing similar results as the normal control subjects. Two routes for voluntary movement are available in the nervous system. The decreased function of basal ganglia due to PD impaired the route from the basal ganglia to the supplementary motor cortex. These data suggest that the route from sensory input to cerebellum to premotor cortex could compensate for the decreased function of the route via the basal ganglia to the premotor cortex. Once change in the motor cortex occurred, such change persisted even after the interruption of training. These phenomena suggest that motor memory can be stored in the motor cortex.

Nitric oxide synergistically potentiates interleukin-1 beta-induced increase of cyclooxygenase-2 mRNA levels, resulting in the facilitation of substance P release from primary afferent neurons: involvement of cGMP-independent mechanisms.

We previously demonstrated that cultured rat dorsal root ganglion (DRG) cells respond to stimulation with interleukin-1 beta (IL-1 beta) by releasing substance P (SP), and this response is regulated via the cyclooxygenase (COX)-2 pathway. In this study, to ascertain the interaction between nitric oxide (NO) and prostaglandins in primary afferent neurons, we investigated the effect of NO on the IL-1 beta-induced release of SP in cultured DRG cells. An NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), did not in itself evoke SP release. However, it potentiated the IL-1 beta-induced release of SP. Similarly, while SNAP did not elicit the expression of COX-2 mRNA, it potentiated the expression induced by IL-1 beta in cultured DRG cells, and this potentiation was significantly suppressed by the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO). Moreover, SNAP also potentiated the expression of COX-2 protein induced by IL-1 beta in cultured DRG cells. The stimulatory effect of SNAP on the IL-1 beta-induced release of SP was completely inhibited on co-incubation with a selective COX-2 inhibitor, NS-398. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a potent inhibitor of soluble guanylate cyclase, did not suppress, and a membrane-permeable cGMP analogue, 8-Br-cGMP, did not mimic the stimulatory effects of SNAP in DRG cells. These results suggest that in cultured DRG cells, NO potentiates the IL-1 beta-induced increase in COX-2 expression via a soluble guanylate cyclase-cGMP-independent pathway, resulting in facilitation of SP release. The interaction between NO and COX in primary afferent neurons might contribute to the change in nociceptive perception in inflammatory hyperalgesia.

(1)H double-quantum filtered MR imaging of joints tissues: bound water specific imaging of tendons, ligaments and cartilage.

The (1)H double-quantum filtered (DQF) NMR and DQF MRI is applied to the joint tissues of rabbits for selective visualization of tendons, menisci and articular cartilage. The (1)H DQF NMR selectively filters double-quantum coherence arising from the (1)H dipolar interaction of the "bound" water in these tissues. The double-quantum creation time dependency of the DQF signal intensity is determined by the molecular environment of the "bound" water. Therefore, each tissue has a unique creation time at which the DQF signal reaches its maximum intensity, tau(max) (Achilles tendon: 0.46 +/- 0.02 ms, patella: 0.55 +/- 0.8 ms, anterior cruciate ligament: 0.60 +/- 0.05 ms, meniscus: 0.78 +/- 0.02 ms, skin: 0.81 +/- 0.07 ms). We have presented the creation-time-contrasted DQF images of the meniscus, patella, foot, and knee joint. Compared with conventional T(2)*-weighted gradient-echo (GRE) MR images, tendons, ligaments, menisci, and articular cartilage were more clearly seen in the DQF MR images. All these tissues were distinctly discriminated from each other by their creation times. DQF MR images of foot and knee joints can selectively demonstrated tendons, ligaments, and cartilage, which make it easier to understand the complicated anatomic structure of joints. Because the DQF NMR signal intensity and tau(max) are sensitive to the order structure of the "bound" water, it might be possible to introduce the creation-time dependent-contrast of (1)H DQF MR images as a new tool for analyzing the changes in the ordered structure of the tissue.

Human corticospinal excitability evaluated with transcranial magnetic stimulation during different reaction time paradigms.

The aim of this study was to evaluate corticospinal excitability of both hemispheres during the reaction time (RT) using transcranial magnetic stimulation (TMS). Nine right-handed subjects performed right and left thumb extensions in simple (SRT), choice (CRT) and go/no-go auditory RT paradigms. TMS, inducing motor-evoked potentials (MEPs) simultaneously in the extensor pollicis brevis muscles bilaterally, was applied at different latencies from the tone. For all paradigms, MEP amplitudes on the side of movement increased progressively in the 80-120 ms before EMG onset, while the resting side showed inhibition. The inhibition was significantly more pronounced for right than for left thumb movements. For the left SRT, significant facilitation occurred on the right after EMG onset. Initial bilateral facilitation occurred in SRT trials with slow RT. After no-go tones, bilateral inhibition occurred at a time corresponding to the mean RT to go tones. The timing of the corticospinal rise in excitability on the side of movement was independent of task difficulty and RT. This suggests that corticospinal activation is, to some extent, in series and not in parallel with stimulus processing and response selection. Corticospinal inhibition on the side not to be moved implies that suppression of movement is an active process. This inhibition is more efficient for right- than for left-side movements in right-handed subjects, possibly because of left hemispheric dominance for movement.

Characteristics of proton NMR T(2) relaxation of water in the normal and regenerating tendon.

The molecular behavior of water in normal and regenerating tendons was analyzed using the transverse relaxation time (T(2)) measured by spin-echo proton nuclear magnetic resonance ((1)H-NMR) spectroscopy at 2.34 T (25 degrees C). A section of the Achilles tendon was dissected from an anesthetized Japanese white rabbit, and its longitudinal axis was oriented at 0, 35, 54.7, 75, and 90 degrees to the static magnetic field. In the normal tendon, the T(2) relaxation of water presented biexponential relaxation and anisotropy in both the long T(2) (5.41 to 6.21 ms) and short T(2) (0.41 to 1.43 ms) components, in which the greatest values were obtained at 54.7 degrees. However, the range of the anisotropy was much narrower than we expected from the (1)H dipolar interaction of water bound to the collagen fibers in the tendon. The apparent fractions of water proton density also varied with orientation: the fraction of the longer T(2) components was at its maximum at 54.7 degrees. These results suggest that a simple two-compartment model could not be applicable to orientational dependency of the T(2) value of the tendon, and the well ordered water in the short T(2) relaxation component may show an elongated T(2) relaxation time that falls in the range of the long T(2) relaxation component at 54.7 degrees. This hypothesis can explain both the narrower range of the T(2) relaxation time and the orientational dependency on the apparent fraction of (1)H density. Regenerating processes of the Achilles tendon were followed for 18 weeks by analyzing the T(2) relaxation time. There is only a long T(2) relaxation time component (21.8 to 28.0 ms) up to 3 weeks after transection. Biexponential relaxation is revealed at 6 weeks and thereafter, whereby (i) the T(2) relaxation times become shorter, (ii) there is anisotropy in the short and long T(2) values, and (iii) the orientational dependency of the apparent fraction of water proton density becomes evident with maturation of the regenerating tendon. From these results, the (1)H T(2) relaxation time of water might be used to monitor the healing process of collagen structures of the tendon non-invasively.

1H double-quantum-filtered MR imaging as a new tool for assessment of healing of the ruptured Achilles tendon.

1H double-quantum-filtered magnetic resonance imaging (DQF MRI) was applied to monitor the healing process of the Achilles tendons in rabbits after tenotomy. DQF MRI provides a new contrast, which is based on the non-zero average of the dipolar interaction caused by anisotropic motion of water molecules, determined mainly by their interaction with the ordered collagen fibers. Tissues are characterized by the dependence of their DQF signal on the DQ creation time, tau. With the use of DQF MRI, higher tissue contrast is obtained between tendon, bone, skin, and muscle. The tendons, which give weak signals in standard MRI techniques, are highlighted in the (1)H DQF image. The image changed dramatically during the healing process of the injured Achilles tendon. These changes matched the phases of the healing process. By using a tau-weighted contrast, the DQF images indicate the part of tendon that has not completely healed, even after the conventional MRI appeared normal. Magn Reson Med 42:884-889, 1999.

Interleukin-1beta induces substance P release from primary afferent neurons through the cyclooxygenase-2 system.

Substance P (SP) is synthesized in the dorsal root ganglion (DRG) and released from primary afferent neurons to convey information regarding noxious stimuli. The effects of the proinflammatory cytokine interleukin-1 (IL-1) beta on the release of SP were investigated using primary cultured rat DRG cells. Recombinant mouse IL-1beta added to the cells at 0.1 ng/ml increased the SP-like immunoreactivity (SPLI) in the culture medium after incubation for 6 h by approximately 50% as compared with that of nontreated DRG cells. The effect of IL-1beta was Ca(2+)-dependent and significantly inhibited by 100 ng/ml IL-1 receptor-specific antagonist (IL-1r antagonist), cyclooxygenase (COX) inhibitors such as 0.1 mM aspirin, 1 microg/ml indomethacin, and 1 microM NS-398 (specific for COX-2), and 1 microM dexamethasone. Furthermore, a 1-h incubation with IL-1beta markedly increased the inducible COX-2 mRNA level, which was inhibited by an IL-1r antagonist and dexamethasone, whereas IL-1beta showed no effect on the level of constitutive COX-1 mRNA. These observations indicated that IL-1beta induced the release of SP from the DRG cells via specific IL-1 receptors, the mechanism of which might involve prostanoid systems produced by COX-2. This could be responsible for the hyperalgesic action with reference to inflammatory pain in the primary afferent neuron to spinal cord pathway.

Subclinical syphilitic hepatitis, which was markedly worsened by a Jarisch-Herxheimer reaction.

Early syphilitic hepatitis is uncommon and tends to be overlooked. However, the diagnosis of this disease is important, because appropriate treatment results in rapid resolution of the hepatitis. We report a case of subclinical early syphilitic hepatitis exaggerated by a Jarisch-Herxheimer reaction. This reaction helped to realize the diagnosis in this case.

Norepinephrine- and K+-induced Mn2+-dependent contractions and the dynamics of intracellular Mn2+ changes in dispersed smooth muscle cells from Ca2+-depleted Mn2+-loaded vas deferens of the guinea pig.

The cellular mechanisms of norepinephrine (NE)-induced Mn2+-dependent contractions were investigated in dispersed smooth muscle cells from guinea pig vas deferens by characterizing the effects of NE and K+ on cell length observed by videotape microscopy and on intracellular Mn2+ and Ca2+ concentration ([Mn2+]i and [Ca2+]i) observed by confocal microscopy. Both stimulants induced slow sustained contraction in Ca2+-depleted, Mn2+-accumulated cells (Mn2+-loaded cells), whereas they induced biphasic contractions in normal cells that were neither Ca2+-depleted nor Mn2+-loaded. In both conditions, the number of cells responding to NE as well as the magnitude of NE-induced contractions increased in a dose-dependent manner. Contractions induced by K+ in Mn2+-loaded strip preparations were markedly smaller than those induced by NE. Although individual K+-induced contractions in responsive Mn2+-loaded cells were as large as those induced by NE, a much smaller percentage of Mn2+-loaded cells was responsive to K+ than to NE. These results are consistent with the idea that the contractions of strip preparations may reflect the magnitude of the contractions of individual cells as well as the percentage of responsive cells in the preparations. Inconsistent with the contractions, the [Mn2+]i rise induced by K+ was larger than that induced by NE, and the percentage of cells responsive to K+ was larger than that responsive to NE. These results suggest that NE may increase the Mn2+ sensitivity of contractile elements.

[A case of acute multifocal motor neuropathy with conduction block after Campylobacter jejuni enteritis].

The patient was a 25-year-old male with acute multifocal motor neuropathy with conduction block (MMNCB) after Campylobacter jejuni enteritis. After having suffered from diarrhea for 3 days, he rapidly developed asymmetrical distal-dominant muscle weakness in all extremities. Sensory disturbance was unremarkable except for slight disturbance in deep sensation. Deep tendon reflexes were normal throughout the course of present illness. CSF analysis revealed increased protein up to 66 mg/dl without pleocytosis. In electrophysiological examinations, persistant multifocal conduction blocks in the motor nerves were predominantly noted in the distal part of the extremities. Serum titers of anti-Campylobacter jejuni antibody, anti-GM1 antibody and anti-GalNAc-GD1a antibody were elevated. Muscle weakness resolved completely within 7 weeks. The sural nerve biopsy did not reveal either axonal degeneration, nor demyelination. These clinical and laboratory findings suggested that this case was most likely an acute type of MMNCB after Campylobacter jejuni enteritis.

Absence of facilitation or depression of motor evoked potentials after contralateral homologous muscle activation.

We have previously described post-exercise facilitation and post-exercise depression of motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS). To determine the presence of post-exercise facilitation after exercise of a contralateral muscle, MEPs were recorded from the resting right extensor carpi radialis (ECR) muscle while the left ECR muscle was activated, then immediately after brief left ECR activation, and, finally, immediately after brief right ECR activation. We repeated the experiment using the first dorsal interosseous (FDI) muscle. To determine the presence of post-exercise depression after exercise of a contralateral muscle, MEPs were recorded from the right ECR after prolonged exercise of the left ECR, followed by right ECR recording after its fatigue. The mean MEP amplitudes from the right ECR and the right FDI after brief activation were 187% and 266% of their pre-exercise values, respectively. There were no significant changes in MEPs recorded from the right ECR or FDI muscles during or immediately after brief activation of their left counterparts. The mean amplitude of MEPs recorded from the right ECR after it fatigued was approximately half the pre-exercise value, but there was no significant change in MEPs recorded from the right ECR after prolonged exercise of the left ECR. Therefore, neither post-exercise facilitation nor post-exercise depression occurred after contralateral homologous muscle exercise.

Effects of transcranial electrical and magnetic stimulation on reciprocal inhibition in the human arm.

We studied the effects of transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS), delivered at intensities below the threshold for evoking an electromyographic response, on the disynaptic and presynaptic phases of reciprocal inhibition in 8 healthy subjects. After TES, the H-reflex evoked in the flexor carpi radialis (FCR) muscle was strongly facilitated when the cortical stimulus was given 4.0-4.5 ms after the test stimulus (median nerve stimulus). TES reduced the disynaptic phase of reciprocal inhibition most strongly when the cortical stimulus followed the test stimulus by 3.0-3.5 ms. TES also reduced presynaptic inhibition, but with a time course that was identical to that of the facilitation of the uninhibited H-reflex. After subthreshold TMS, the facilitation of the H-reflex showed at least 2 peaks, one occurring when the cortical stimulus was given 2 ms after the test stimulus and the other when the cortical stimulus followed the test stimulus by 0.5 to -1.5 ms. The effects of TMS on the 2 phases of reciprocal inhibition were similar, and in both cases the disinhibitory effects had essentially the same time course as the facilitatory effect of TMS on the uninhibited H-reflex. The different effects of TES on the 2 phases of reciprocal inhibition provide evidence of the presynaptic nature of the second phase. The absence of a difference in the effect of TMS on the 2 phases could be due to the more temporally dispersed descending volley after TMS.

Decreased postexercise facilitation of motor evoked potentials in patients with chronic fatigue syndrome or depression.

We studied the effects of exercise on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in 18 normal (control) subjects, 12 patients with chronic fatigue syndrome, and 10 depressed patients. Subjects performed repeated sets of isometric exercise of the extensor carpi radialis muscle until they were unable to maintain half maximal force. MEPs were recorded before and after each exercise set and for up to 30 minutes after the last set. The mean amplitude of MEPs recorded from the resting muscle immediately after each exercise set was 218% of the mean pre-exercise MEP amplitude in normal subjects, 126% in chronic fatigue patients, and 155% in depressed patients, indicating postexercise MEP facilitation in all three groups. The increases in the patient groups, however, were significantly lower than normal. The mean amplitudes of MEPs recorded within the first few minutes after the last exercise sets in all three groups were approximately half their mean pre-exercise MEP amplitudes. This postexercise MEP depression was similar in all groups. We conclude that postexercise cortical excitability is significantly reduced in patients with chronic fatigue syndrome and in depressed patients compared with that of normal subjects.

Abnormal cortical motor excitability in dystonia.

To assess the excitability of the motor system, we studied 11 patients with task-specific dystonia and 11 age-matched normal subjects. The dominant side was affected in nine of the patients. We delivered transcranial magnetic stimuli at different stimulus intensities and with different levels of muscle facilitation to the side contralateral to the side of electromyographic recording, and recorded motor evoked potentials (MEPs) from the flexor carpi radialis muscles bilaterally. The threshold intensity for eliciting MEPs at rest did not differ between patients and normal subjects. We compared the affected side in patients with the dominant side in normal subjects. With facilitation, the percentage of the area of the MEP to the M wave (MEP area%) was similar in both groups at low stimulus intensities, but with increasing stimulus intensity the increase in the MEP area% was greater in patients than in normal subjects (ANOVA, p < 0.001). The increase in MEP area% was similar in both groups with increasing facilitation levels. The duration of the silent period was similar in patients and normal subjects. We conclude that cortical motor excitability is increased in dystonia.